Lung cancer is the most common cause of cancer related deaths in both men and women in the United States (Jemal, A., Cancer Statistics, 2007, CA Cancer J. Clin. 2007; 57: 43-66). The majority of patients (80%) will have non-small cell lung cancer (NSCLC) and will present with advanced stage lung cancer which is incurable with currently available therapies. For patients with advanced NSCLC, chemotherapy is the mainstay of treatment and is associated with a median survival of 8-10 months. These figures have changed very little in the last 25 years.
An important research goal has been to understand critical molecular alterations in NSCLC which may lead to the identification of effective therapies for NSCLC patients. A compelling example of this approach was the discovery of somatic mutations in the epidermal growth factor receptor (EGFR) and their association with dramatic clinical benefits in patients with EGFR mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs). EGFR TKIs have been shown to be effective therapeutic agents for patients with non-small cell lung cancer (NSCLC) with tumors that harbor somatic activating mutations in EGFR. In prospective clinical trials, 60-80% of NSCLC patients with EGFR mutations, exhibited tumor regression when treated with gefitinib or erlotinib lasting on average 9-13 months (Inoue, A., et al. J Clin Oncol 2006; 24: 3340-6; Paz-Ares, et al. Journal of Clinical Oncology 2006; 24: Abstract 7020; Okamoto, I., et al. Journal of Clinical Oncology 2006; 24: Abstract 7073; Sutani, A., et al. Journal of Clinical Oncology 2006; 24: Abstract 7076; Morikawa, N., Journal of Clinical Oncology 2006; 24: Abstract 7077; Sequist, L. V., et al. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings 2007; 25: a7504).
In a phase III clinical trial chemotherapy naïve NSCLC patients with EGFR mutations had a significantly longer progression free survival when treated with an EGFR TKI than with conventional chemotherapy. EGFR mutations are only found in 10-15% of all NSCLC patients. Responders typically relapse 6-19 months after taking EGFR TKIs as a consequence of becoming resistant to the inhibitors. There is currently no FDA approved therapy for NSCLC patients that develop resistance to EGFR TKIs. The most common mechanism of resistance is mutation of the EGFR ATP-binding site in a manner that renders the site less sensitive to drug inhibition. For example the most common resistance mutation occurs at the gatekeeper T790M position. This mechanism of resistance is found in 50% of EGFR mutant NSCLC patients that develop resistance to EGFR kinase inhibitors gefitinib or erlotinib. Another mechanism of resistance involves upregulation of alternative signal transduction pathways.
More recently the EML4-ALK fusion protein has been found to be an oncogenic driver in non-small cell lung cancer and the first targeted therapy, crizotinib has been approved for the treatment of this patient subset by the FDA. Cancer genomics efforts have recently also resulted in the identification of oncogenic driver mutations in two other receptor tyrosine kinases: ROS1 and FGFR.
There is a need for the development of small molecule inhibitors that potently and selectively inhibit the activity of wild-type and mutant forms of EGFR, FGFR, ALK, ROS1, JAK, BTK, BLK, ITK, TEC, and TXK for the treatment of cancer, including NSCLC.